The Ras proteins are a family of guanine nucleotide binding GTPases that play a pivotal role in mediating cell growth, differentiation and development. (Barbacid, Annual Review of Biochemistry, Vol. 56, p. 779 (1987)). In mammalian cells, there are three ras genes that encode four Ras proteins, H, N, KA and KB-Ras. (E. C. Lerner et al., Anti-Cancer Drug Design, Vol. 12, pp. 229-238 (1997)). Mutations in Ha-ras, Ki-ras and N-ras, and the overexpression of Ras has been observed in approximately 30% of all human cancer tissues. (Lerner et al., S. L. Graham, Exp. Opin. Ther. Patents, Vol. 5, no. 12, pp. 1269-1285 (1995); T. Hiwasa, Oncology Reports, Vol. 3, pp. 7-14 (1996); S. L. Graham and T. M. Williams, Exp. Opin. Ther. Patents, Vol. 6, no. 12, pp. 1295-1304 (1996)). Although several steps are involved in modifying Ras proteins, farnesylation is the only step which is required and sufficient for Ras transforming activity. (E. C. Lerner et al.) Therefore, farnesyl-transferase (FTase) serves as an attractive target for the development of a potential new class of anti-cancer agents. (E. C. Lerner et al.) It has been noted that routes to inhibitors of Ras farnesylation are apparent from an examination of the substrate specificities of the enzyme. One can design analogs either of the lipid, or of the peptide sequence to which the lipid is transferred. Such compounds must be stable, and readily cross the cell membrane to gain access to the cytosolic transferase. (J. E. Buss and J. C. Marsters, Jr., Chemistry and Biology, Vol. 2, pp. 787-791 (1995)).
Compounds that incorporate substituted-piperazinone moieties have been observed to be farnesyltransferase inhibitors (WO 96/30343, published on Oct. 30, 1996). It is therefore desirable to discover a process for making substituted piperazinones that is efficient and operationally facile. Many prior syntheses for 1-aryl-piperazinones have required a 5-step procedure. Syntheses previously described require multiple isolation steps and high temperatures for installation of an ethylamine equivalent. These processes have also utilized expensive reagents. The overall yield from the previously described syntheses are typically less than 50%. Other processes useful for synthesizing beta-lactams from a hydroxyamine in the presence of a tertiary amine have been described. However, such a synthesis is dependent on the amine being tertiary, or protected, and not secondary or primary, to avoid competing aziridine formation. (G. M. Salituro et al., J. Am. Chem. Soc. 1990, Vol. 112, pp. 760-770). There is an example of the synthesis of a bicyclic piperazinone via a Mitsunobu reaction in the presence of a protected tertiary amine. (P. S. Hadfield et al., J. Chem. Soc., Perkins Trans. 1, 1997, pp. 503-509). Typically, the products synthesized via a Mitsunobu reaction require purification via column chromatography. Column chromatography has been used in such instances to separate the reaction product from the phosphine oxide and hydrazine by-products. (D. Hughes, Organic Reactions, Vol. 42, pp 335-656, (1992)). It is therefore desirable to design a process which isolates and purifies the synthesized compounds in one step, without the use of column chromatography.
It is therefore an object of this invention to provide a process for the synthesis of substituted piperazinones that is less time-consuming and more efficient.
It is a further object of this invention to provide a process for the synthesis of substituted piperazinones that employs readily available reagents and uses tertiary amines which are not protected.
It is a further object of this invention to provide a process for the synthesis of substituted piperazinones that synthesizes the compounds via cyclodehydration in the presence of secondary amines.
It is a further object of this invention to provide a process for the synthesis of substituted piperazinones that results in an overall yield which is higher than 50%.